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Nat Commun. 2017 May 31;8:15654. doi: 10.1038/ncomms15654.

Oligolysine-based coating protects DNA nanostructures from low-salt denaturation and nuclease degradation.

Ponnuswamy N1,2,3, Bastings MMC1,2,3, Nathwani B1,2,3, Ryu JH1,2,3,4, Chou LYT1,2,3, Vinther M5, Li WA3,6, Anastassacos FM1,2,3, Mooney DJ3,6, Shih WM1,2,3.

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Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Wyss Institute for Biologically Inspired Engineering at Harvard, Boston, Massachusetts 02115, USA.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
Centre for DNA Nanotechnology, Interdisciplinary Nanoscience Center, iNANO, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark.
School of Engineering and Applied Sciences, Harvard University, Cambridge Massachusetts 02138, USA.


DNA nanostructures have evoked great interest as potential therapeutics and diagnostics due to ease and robustness of programming their shapes, site-specific functionalizations and responsive behaviours. However, their utility in biological fluids can be compromised through denaturation induced by physiological salt concentrations and degradation mediated by nucleases. Here we demonstrate that DNA nanostructures coated by oligolysines to 0.5:1 N:P (ratio of nitrogen in lysine to phosphorus in DNA), are stable in low salt and up to tenfold more resistant to DNase I digestion than when uncoated. Higher N:P ratios can lead to aggregation, but this can be circumvented by coating instead with an oligolysine-PEG copolymer, enabling up to a 1,000-fold protection against digestion by serum nucleases. Oligolysine-PEG-stabilized DNA nanostructures survive uptake into endosomal compartments and, in a mouse model, exhibit a modest increase in pharmacokinetic bioavailability. Thus, oligolysine-PEG is a one-step, structure-independent approach that provides low-cost and effective protection of DNA nanostructures for in vivo applications.

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